4a-Phenyl(or substituted phenyl)octahydro-1H-2-pyrindines are disclosed in Belgian Pat. No. 860,314 as being useful analgesic agents having mixed agonist-antagonist properties. These compounds can be represented by the following formula: ##STR1## wherein R is H, (C.sub.1 -C.sub.8)alkyl etc. and R.sup.1 is H, alkoxy, OH or alkanoyloxy. 4a-Phenyloctahydro-1H-2-pyrindines of the above formula can be prepared by the following reaction sequence: A 2-arylcyclohexanone is alkylated at the 2-position by reaction with an .alpha.-halo acetate in the presence of base. The product of this reaction, a 2-aryl-2-alkoxycarbonylmethylcyclohexanone, is next formylated at the 6-position by reaction with ethyl formate in the presence of metallic sodium. The 2-aryl-2-alkoxycarbonylmethyl-6-formylcyclohexanone thus prepared is next reacted with p-tosylazide to provide a 2-aryl-2-alkoxycarbonylmethyl-6-diazocyclohexanone. Photolysis of the diazo compound results in a ring contraction, the product of the reaction being a 2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentane. Hydroxylsis of this compound provides the corresponding diacid, 2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane. Cyclization of this diacid derivative with an acid halide such as acetyl chloride provides the corresponding anhydride, a 4a-aryl-tetrahydro-2,6-dioxocyclopenta[c]pyran. Reaction of this dioxopyran with ammonia or a primary amine (R.sup.2 -NH.sub.2) yields a cyclic imide; to wit, a 1,3-dioxo-4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. The dioxopyrindine can then be reduced as with lithium aluminum hydride to yield a 4a-aryl-octahydro-1H-2-pyrindine of formula I. If the product of the synthesis produces a secondary amine, (R is H), other N-derivatives can be prepared as follows:
The secondary amine can be alkylated as with methyl iodide or phenethylbromide in a standard alkylation procedure to yield an N-alkyl (or substituted alkyl) derivative or may be acylated as by cyclopropylcarboxyl chloride to yield a 2-acyl derivative which can in turn be reduced as with lithium aluminum hydride to an alkyl yielding, in this instance, an N-cyclopropylmethyl derivative.
4a-Aryl-trans-dl-decahydroisoquinolines of Formula II below are described in Belgian Pat. No. 802,557 and in a series of U.S. Pat. Nos. 4,001,247; 4,001,248; 4,029,796 (each of which describes the preparation of both cis and trans- compounds); and U.S. Pat. No. 4,100,166, which describes the preparation of certain cis- derivatives corresponding to the trans- derivatives of the Belgian patent. ##STR2## wherein R and R.sup.1 have substantially the same meaning as hereinabove.
U.S. Pat. No. 4,001,247 describes several methods of preparing decahydroisoquinolines. The first procedure begins with the reaction of a 2-arylcyclohexanone with acrylonitrile to yield a 2-phenyl-2-(.beta.-ethyl)cyclohexanone. The nitrile group is hydrolyzed to a carboxylic acid function, the corresponding azide prepared and the azide converted to the isocyanate. Treatment of the isocyanate with acid yields a 3a-aryl-2,3,3a,4,5,6,7-heptahydroindole. Next the heptahydroindole is acylated to yield a N-methyltetrafluoroborate quaternary salt. The reaction of this salt with diazomethane produces a salt of a 1-azonia-1-methyl-4-aryltricyclo[4,2,1,0.sup.1-9 ]decane, rearrangement of which by treatment with heat and alkali produces a 2-methyl-4a-aryl-2,3,4,4a,5,6,7,8-octahydroisoquinoline. The double bond in this compound can be hydrogenated to yield either a cis- or trans-decahydroisoquinoline. In addition, the methyl group can be removed to yield a secondary amine which can be realkylated to yield a variety of N-substituted-4a-aryldecahydroisoquinolines, as set forth above for the corresponding 4a-aryloctahydro-1H-2-pyrindines.
A second reaction sequence disclosed in U.S. Pat. No. 4,100,166 involves the alkylation of a 2-arylcycloheptanone with bromoacetic ester to yield a 2-aryl-2-(ethoxycarbonylmethyl)cycloheptanone. This compound is formylated to yield a 7-formyl derivative, treatment of which with p-tosylazide yields the corresponding 7-azido compound. Treatment of this azido compound with methanol results in a molecular rearrangement, the ultimate product of which is a 2-aryl-2-ethoxycarbonylmethylcyclohexanecarboxylic acid ester, isolated as a mixture of cis- and trans-derivative. Saponification of the diester followed by treatment with an acid chloride yields the corresponding cyclic anhydride named as a cis(or trans)-3,4,4a,5,6,7,8,8a-octahydro-1,3-dioxo-1H-2-benzopyran. This intermediate is similar to those employed for the preparation of the pyrindines as described in Belgian Pat. No. 860,314 and the same series of reactions; i.e., reaction with a primary amine followed by reduction of the resulting imide, yields directly the cis (or trans)-4a-aryl-N-substituted-decahydroisoquinoline.
Brittelli and Ripka in Belgian Pat. No. 802,557 disclose a still different method of preparing the 4a-aryldecahydroisoquinolines. This procedure begins with a 2-cyano-3-aryl-3-ethoxycarbonylmethylcyclohexene which can be cyclized in the presence of acid to yield a 4a-aryl-1,3-diox-1,2,3,4,4a,5,6,7-octahydroisoquinoline. This imide is customarily alkylated to yield an N-substituted product prior to reduction of the 8,8a-double bond (which produces a trans-derivative) and finally by removal of the dioxo groups by reduction with lithium aluminum hydride. Reduction of the 8,8a-double bond can also take place prior to reduction of the imide and the trans-dioxo-decahydroisoquinoline can be epimerized to the corresponding cis derivative.
Each of the above synthetic procedures involves a large number of steps and many of these steps afford the possibility of by-product formation. Furthermore, one of the procedures for preparing the above decahydroisoquinolines involves the use of the toxic and explosive substance, diazomethane. In addition, the procedures outlined above for the preparation of the decahydroisoquinolines have been found to be inoperative for the preparation of octahydropyrindines.
It is an object of this invention to provide a short and simplified process for the preparation of either octahydropyrindines or decahydroisoquinolines carrying an aryl substituent at the bridge-head carbon, which synthesis can provide the desired products in either cis- or trans configuration.